Recent observations suggest that abnormal conformations of proteins that are normal constituents of the dopaminergic neuron participate in death of this cell type in Parkinson Disease (PD). Some rare forms of PD can be linked to mutations that cause such proteotoxicity, either directly by affecting the primary structure of the protein converting it to a proteotoxin (e.g. a-SYN mutations) or indirectly, by affecting cellular processes that impact on the accumulation of proteotoxins (e.g. PARK2 mutations). However, such mutations are found in only a small fraction of PD patients, raising the question of how proteotoxicity is triggered in other cases. Recent experiments from our lab indicate that 6-hydroxydopamine and Rotenone, toxins implicated in experimental and environmental PD, cause an imbalance between the folding capacity of the endoplasmic reticulum (ER) and the load of client proteins placed on that organelle (so called ER stress). Uncompensated ER stress can promote proteotoxicity by competing for limited capacity of the ubiquitin proteasomal system and by producing ROS that can alter protein structure. Neurons are naturally prone to ER stress because of their extensive secretory activity and because of their highly elaborate membrane enclosed processes, which must be maintained by high rates of ER trafficking of client proteins. ER stress is normally counteracted by the unfolded protein response (UPR), an adaptive cellular signaling pathway that is activated specifically by ER stress. Impaired UPR signaling sensitizes cells specifically to the effect of ER stress. Therefore, we propose to test the role of ER stress in the development of PD by examining the effect of mutations that impair signaling in the UPR on an established model of experimental PD and on a component of genetic PD. We will determine if in mice lacking the key UPR gene, PERK dopaminergic neurons are hypersensitive to 6-hydroxydopamine. We will seek to identify the defect in ER function imparted by 6-hydroxydopamine and relate it, if possible, to the known ability of the toxin to inhibit mitochondrial complex-1. Finally, we will critically examine PARK2's role in ER-associated degradation of proteins. If the proposed experiments support a role for ER stress in the development of PD, this will effect a paradigmatic shift in our thinking about the pathogenesis of this common disorder.